This new project was just funded in early spring of 2003 and a postdoctoral fellow started in June 2003. We have completed planning and received approval for the animal protocols. The project has two general aims. Aim 1 is to determine the relationship between cardiotoxicant induced alterations in cardiac function and changes in biomarkers (morphologic and gene expression). We will treat rats and mice with suspected cardiotoxic drugs and correlate cardiac function, morphology and changes in gene expression. These studies will allow us to determine, for example, if contractile dysfunction correlates with morphologic loss of troponin. Aim 2 will provide information regarding common mechanisms of cardiotoxic agents. Drugs that interrupt mitochondrial function or generate reactive oxygen species frequently lead to cardiotoxicity. We plan to test this hypothesis. For example we will treat animals with antioxidants to see if this ameliorates the cardiotoxicity. We can also study transgenic animals with altered mitochondrial function or altered antioxidant capabilities (e.g. overexpression of SOD) to see if they have altered development of cardiotoxicity. We will measure physiological parameters such as heart rate, left ventricular developed pressure, rate of contraction and rate of relaxation, coronary flow rate, high energy phosphates, and intracellular pH under baseline conditions and in response to increased cardiac workload (e.g. pacing to increased heart rate, or adrenergic stimulation). These studies will employ a Langendorff perfused heart model. Rabbits, rats and mice can be studied with this model. After monitoring function, hearts can be fixed in formalin for morphologic studies or frozen for RNA isolation for gene profiling studies. Transgenic mice can also be used to test specific hypotheses. Rats will be dosed with the drugs (AZT, adriamycin and bis (2-chloroethoxy)methane), according to NTP protocols. At appropriate time points samples will be taken for physiological measurements and biomarkers (histology and gene profiling).